tbuckley/cabot-search huggingface dataset:
Phase II trial of maximal ablative irradiation because of encasement (MAIBE) for patients with potentially resectable locally advanced pancreatic cancer.
Authors: Marsha Reyngold, Wei Alice, Eileen Mary O'Reilly, Michael Ian D'Angelica, Jeffrey A. Drebin, Kevin Soares, T. Peter Kingham, Vinod P. Balachandran, Anna M. Varghese, Wungki Park, Danny Khalil, Kenneth H. Yu, Melissa Zinovoy, John J Cuaron, Carla Hajj, Paul Bernard Romesser, Abraham Jing-Ching Wu, Zhigang Zhang, William R. Jarnagin, Christopher H. Crane
Journal: Journal of Clinical Oncology (2023)

710 Background: For patients with localized but not immediately resectable pancreatic adenocarcinoma (PDAC), the role for local therapy remains undefined. Phase II MAIBE trial studied ablative radiation (A-RT) followed by consideration of surgery for patients with locally advanced pancreatic cancer (LAPC) who remain unresectable after induction chemotherapy. Methods: Participants with histologically confirmed PDAC judged unresectable by multidisciplinary review using NCCN definition after completing 3-6 months of mFOLFIRINOX (FFX) or Gemcitabine/Nab-paclitaxel (GN) were eligible. They received hypofractionated A-RT (either 67.5Gy in 15 fractions or 75Gy in 25 fractions based on anatomy) with concurrent capecitabine followed by consideration of resection within 1-3 months. Primary endpoints included resectability (80% power to detect resectability improvement from 15% in historical controls to 30% with α = 0.05) and overall survival (OS) from A-RT. Secondary endpoints included safety of surgical resection after ablative RT using 90-day Clavien-Dindo Classification of adverse events (AE). Results: Between 6/2018 and 4/2022, 47 eligible participants underwent A-RT. Median age was 67 (range, 50-80) years, 24 (51%) were male with a median tumor size of 3.95 (1.6 – 8.3) cm and CA19-9 of 92 ( &lt; 1-1601) U/mL. Forty-four patients (94%) received at least 1 cycle of FFX with a median duration of chemotherapy (FFX or GN) of 3.5 months (1.0 – 9.4). Sixteen (34%) underwent a laparoscopy and 12 (26%) underwent a resection (Pancreaticoduodenectomy, N = 11; distal pancreatectomy, N = 1) at a median time of 3.2 months (1.9-16.9 months) from start of A-RT. The rate of resection satisfied our prespecified boundary of 11. R0 rate was 58.3%. Two-year OS from A-RT for the entire cohort was 38.9% (95% CI, 21.9 – 55.6%), including 37.1% (18.5 - 55.8%) in non-surgical and 39.4% (7.0- 72.1%) in surgical groups. There were no deaths within 90 days of surgery and 9 surgical AEs were recorded in 6 participants, including grade 1 (n = 1), grade 2 (n = 5), grade 3 (n = 2) and grade unknown (n = 1). Conclusions: In patients with LAPC and no metastatic disease after 3-6 months of chemotherapy, A-RT results in a favorable rate of resection without excess surgical toxicity. Promising 2-year OS rates were noted in both resected and non-resected patients. Clinical trial information: NCT03523312 .
APOLLO: A randomized phase II double-blind study of olaparib versus placebo following curative intent therapy in patients with resected pancreatic cancer and a pathogenic <i>BRCA1, BRCA2</i> or <i>PALB2</i> mutation—ECOG-ACRIN EA2192.
Authors: Kim Anna Reiss, Sung Chul Hong, Anup Kasi, Eileen Mary O'Reilly, Shishir K. Maithel, Xin Yao, Stanley R. Hamilton, Ben Boursi, Michael J. Pishvaian, Samuel J Klempner, Susan M. Domchek, Paul J. Catalano, E. Gabriela Chiorean, Philip Agop Philip, Peter J. O'Dwyer
Journal: Journal of Clinical Oncology (2023)

TPS763 Background: A meaningful subset of PDAC is characterized by a homologous recombination deficiency (HRD). The most well-defined patients within this group are those with pathogenic variants in BRCA1, BRCA2 and PALB2. In the metastatic setting, PARP inhibitor maintenance provides a progression-free survival benefit after a period of platinum based chemotherapy 1,2 , but the role of PARP inhibitors in the curative intent setting is undefined. The OlympiA study established one year of olaparib as the standard of care for patients with BRCA-related, early stage breast cancer who completed all other curative-intent treatment 3 . Therefore, we have designed a randomized, phase II double-blind study of one year of olaparib vs placebo in patients with pancreatic cancer and a germline or somatic variant in BRCA or PALB2 who have completed all curative intent therapy. Methods: We have enrolled and treated 23 of 152 planned patients on study NCT 04858334/EA2192. Eligibility criteria include: a pathogenic germline or somatic variant in BRCA1, BRCA2 or PALB2 as determined by local laboratory (central review required); completion of curative-intent resection and ≥ three months of multi-agent chemotherapy; no evidence of recurrent disease. At enrollment, patients must be within 12 weeks of their last anti-cancer intervention. Patients are randomized 2:1 to receive oral olaparib 300 mg twice daily or placebo for 12 28-day cycles. The primary endpoint is relapse-free survival. Overall survival is a secondary endpoint. Tumor tissue, fecal material (for microbiome analysis) and serial ctDNA samples are being collected. 1.Golan T, Locker GY, Kindler HL: N Engl J Med 381:1492-1493, 2019. 2. Reiss KA, Mick R, O'Hara MH, et al: J Clin Oncol 39:2497-2505, 2021. 3. Tutt ANJ, Garber JE, Geyer CE, Jr.: N Engl J Med 385:1440, 2021. Clinical trial information: NCT04858334 .
Evolution of pancreatic ductal adenocarcinoma diagnosis during the last decade.
Authors: Roberto Jiménez Rodríguez, Irene Gonzalez Caraballo, Rocío Martín Lozano, Manuel Alva Bianchi, Mónica Benavente de Lucas, María Palma Gómez, Marc Ariant Cañete Muñoz, Bárbara Lobato Delgado, Victoria Tirado Anula, Blanca Morón García, Magdalena Ruiz Zamorano, Ivan Marquez-Rodas, Isabel Echavarria Diaz Guardamino, Gabriela Torres Pérez-Solero, Aitana Calvo Ferrándiz, Laura Ortega, Jose Manuel Soria, Pilar Garcia-Alfonso, Miguel Martin, Andrés J. Muñoz Martín
Journal: Journal of Clinical Oncology (2023)

670 Background: Pancreatic Ductal Adenocarcinoma (PDAC) has historically been an important diagnostic and therapeutic challenge. The multidisciplinary approach and new diagnostic techniques’ implementation have modified this process. Methods: We conducted a retrospective analysis based on clinical data of patients with PDAC between the years 2010 to 2021, analyzing the diagnosis and initial treatment evolution. Results: 673 patients between 2010-2021 with a suspected diagnosis of pancreatic adenocarcinoma were reviewed. Most of them were metastatic (n=362; 53.8%), followed by locally advanced unresectable (n=166; 24.7%) and resectable or borderline resectable (n=145; 21.5%). Regarding the pathological diagnosis, it was not possible in 62 patients (9.2%), varying over time from 21.2% in 2010-2012 to 1% in 2019-2021 (p&lt;0,0001). Moreover, the number of biopsies has decreased with a mean number of biopsies to obtain a pathological diagnosis of 1.55 (2010-2012) vs 1.31 (2019-2021). During this last period, most of the diagnoses were made by cytological analysis (61.4%; n=121). Specifically in the 2019-2021 patients subgroup, we found that 18 NGS (9,1%) were performed in this period (solid tumor), with 4 patients having actionable mutations (22.2%; 3 KRAS G12C). Germline (g) mutational panels were carried out in 89 patients, finding only 9 positive cases (10.1%), being 3 of them gBRCA1/2 mutated (3,4%). In our study, a decrease in palliative management was evidenced over time. In 2010-2012, 28,8% of patients received exclusively palliative care against 9,6% in 2019-21 (p&lt; 0.0001). An increase in PDAC diagnosis was observed since 2010, 44 patients/year in 2010-12 vs. 66 patients/year in 2019-21 (including COVID-19 pandemic period). All previous results are summarized. Conclusions: The diagnosis of PDAC has changed throughout the last decade, increasing the percentage of patients with a pathological diagnosis without increasing the number of invasive procedures. The number of patients suitable for anti-cancer therapy has also increased among time. In our cohort, the implementation of molecular testing would change the therapeutic approach in more than 20% of patients.[Table: see text]
Metronomic oral cyclophosphamide as maintenance therapy in metastatic pancreatic ductal adenocarcinoma.
Authors: Michele Reni, Giulia Orsi, Umberto Peretti, Marina Macchini, Anna Maria Militello, Massimo Falconi, Stefano Cascinu
Journal: Journal of Clinical Oncology (2023)

716 Background: Metastatic Pancreatic Ductal Adenocarcinoma (mPDAC) has a grim prognosis, with limited therapeutic options. In this context, treating patients (pts) with chemotherapy (CT) till progression is not supported by scientific evidence and must be weighed against quality of life impairment and cumulative toxicity. Therefore, we explored the role of metronomic oral cyclophosphamide (mCTX) as maintenance therapy (MT) in mPDAC pts. Methods: Any age mPDAC pts, with Karnofsky performance status &gt;60 and wild-type germline BRCA1-2, who were progression-free after at least 6 months of any regimen and line CT and received mCTX (50 mg/die) MT between August 2020 and July 2022, were included in the analysis. An historical cohort (HC) of mPDAC pts, who were progression-free after 6 months of 1st-line platinum-based combination CT and did not receive MT between 2000 and 2016, was considered for exploratory comparison. Progression-free and Overall Survival (PFS and OS) were calculated from last CT administration for both cohorts. Results: 41 and 122 pts were included in mCTX and HC, respectively. Median PFS was 4.1 (range 1.5-18.4) and 3.1 (1-141) months for mCTX and HC, respectively (p= 0.003). PFS rates at 6 and 12 months were 34.7% and 11.1% in the mCTX cohort, 18.9% and 6.6% in the HC. Median OS was not reached (range 1.5-25) and 10.2 (1.3-142) months for mCTX and HC, respectively (p= 0.002). OS rates at 6 and 12 months were 96.9% and 74.6% in the mCTX cohort, 74.5% and 46.9% in the HC. Factors associated with longer PFS in the mCTX cohort were normal CA19.9 at CT start (p= 0.006), female gender (p= 0.036), no liver metastases (p= 0.01), normalized CA19.9 after CT (p= 0.01). Only 2 pts receiving mCTX had Grade 3 toxicity. Conclusions: mCTX MT extends PFS and OS of mPDAC pts not progressing after at least 6 months of CT with unremarkable toxicity in our exploratory non-randomized analysis.[Table: see text]
Mutation status of full <i>RAS</i> and <i>BRAF</i> in 169 Moroccan patients with colorectal cancer.
Authors: Sara El zaitouni, Abdelilah Laraqui, Meriem Ghaouti, Asmae Benzekri, Fouad Kettani, Hicham El Annaz, Rachid Abi, Mohamed Rida Tagajdid, Safae El Kochri, Idriss Amine Lahlou, Rabii Ameziane El Hassani, Khalid Ennibi
Journal: Journal of Clinical Oncology (2023)

216 Background: Morocco has the highest cancer mortality rate in MENA Countries. Colorectal cancer (CRC) is classified as the first digestive cancer and remains a burden in Morocco. According to the data on GLOBOCAN 2020, there were 4324 new CRC patients and 2374 deaths, accounting for 7.3% and 2.8% of all cancers, respectively. Our study aimed to investigate the frequency of the full RAS ( KRAS, NRAS) and BRAF genes in CRC patients from Morocco and their possible associations with clinico-pathological features. Methods: Archived FFPE of 169 CRC patients were screened for KRAS, NRAS and BRAF mutations by Idylla technology. Results: Full RAS mutations were identified in 46.1% (42% in KRAS, 4.1% in NRAS). In KRAS gene, exon 2 mutations accounted for 84.5% (69% in codon 12, 15.5 % in codon 13). Within codon 12, KRAS G12D and G12C were more frequently detected (29.5% and 16.9%, respectively). Detection of KRAS mutations, and particularly G12D and G12C subtypes, are of large significance for CRC patients, have possible therapeutic implications. Within codon 13, the most frequently observed mutation was G13D (15.5 %). Outside exon 2, the mutation rate was 35.1% (8.4% in exon 3 and 26.7% in exon 4). Concurrent KRAS mutations were identified in 8 cases, which suggests that multiple mutations can occur in the same or different codons. In NRAS gene, the mutation rates of exon 2 and 3 were 71.4% and 57.1% respectively. G13V and Q61K were the most common mutations, accounting for 28.6 % of each. Concurrent KRAS mutations were identified in 2 cases. Of the 169 samples, mutations in the BRAF gene at V600E were detected in 3.5%. Combined mutational analysis of KRAS, NRAS and BRAF was able to identify 49.6% of patients with CRC as likely non-responders to anti-EGFR therapy. There was an association between KRAS mutations and age, which were higher in the age group&gt;50 years old (p=0.022). Tumors in the left colon (36.61%) are more likely to harbor mutations in KRAS than the rectum (19.7%) in both sexes. The adenocarcinoma well-differentiated was the most frequent for patients with KRAS mutations (54.9%). No significant clinicopathologic correlations with NRAS and BRAF mutations were identified. Conclusions: Beside established anti-CRC treatment, better understanding of the causality of CRC can be established by combining epidemiology and genetic/epigenetic on CRC etiology in Morocco. This approach may be able to significantly reduce the burden of disease in the country. Moreover, the Moroccan government should develop policy on CRC prevention and public health programs which may serve as a feasible setting to increase public awareness on lifestyle risk factors.
Assessment of immunoscore and MRI tumor regression grade to predict complete pathologic response in patients with locally advanced rectal cancer: Data from phase II Averectal study.
Authors: Ali Shamseddine, Ahmad Machmouchi, Mustafa Natout, Rim Turfa, Joseph Gergi Kattan, Sally Naji Temraz, Ayman Tawil, Mousa Elkhaldi, Omar Jaber, Rula Amarin, Tala Awabdeh, Maya Charafeddine, Monita Al Darazi, Hero Hussain
Journal: Journal of Clinical Oncology (2023)

212 Background: In patients with locally advanced rectal cancer (LARC), magnetic resonance imaging is the most accurate non-invasive staging tool, enabling response assessment to total neoadjuvant therapy. Wang et al had reported that 46.6% of patients with Magnetic Resonance Tumor Regression Grade 1 (mrTRG=1; complete radiologic response) achieved pathologic complete response (pCR; no residual tumor cells). We reported previously in a Phase II Averectal study the correlation between pre-treatment biopsy Immunoscore (IS) and pCR probability (68% ± 22 SD in patients with a high IS as opposed to 52% ± 22 SD in patients with a low IS; P=0.036). This study explores the value of combining IS and mrTRG to predict pCR among LARC patients. Methods: This is an open-label, single-arm multicenter stage-2 phase II study investigating the efficacy and safety of 5 fractions of short course radiotherapy, followed by 6 cycles of mFOLFOX-6 plus avelumab, followed by Total Mesorectal Excision (TME), in patients with LARC. Mean density percentiles of CD3 and CD8 positive T cells infiltrating the tumor and the invasive margin in baseline tissue samples were used to calculate IS (62% is considered the cutoff between high and low IS). Baseline and post treatment MRI were reviewed by two independent radiologists to measure mrTRG and other variables. Results: Between July 2018 and October 2020, 44 patients were accrued, out of which 40 (90%) completed at least 1 cycle of mFOLFOX/Avelumab and underwent TME. Of the 40, 36 (90%) had baseline IS, mrTRG (pre-post treatment) and pTRG (pathologic Tumor Regression Grade) assessed. Out of 36, 15 (41.6%) achieved pCR, 24 (66.7%) had mrTRG=1 and 22 (61%) had high IS. Of the high IS (n=22) patients, 10 (45.45%) achieved pCR. Also, out of 24 patients with mrTRG=1, 11 (45.8%) attained pCR. Most importantly, of the patients with combined high IS and mrTRG=1 (n=14), 11 (78.6%) achieved pCR. In patients with both mrTRG=1 and high IS, pCR rate was 78.6% (11/14). This result is significantly different from pCR rate for patients with either high IS (10/22, 45.45%) or mrTRG=1 (11/24, 45.8%) with P=0.0247 and P=0.0243 respectively. Conclusions: Combining both IS and mrTRG achieved a promising predictive value for pCR in LARC and therefore upon further validation may be potentially used for patient selection in non-operative management strategies. Clinical trial information: NCT03503630 .
Comparative analyses of intratumoral microbiome with diet in patients with early- vs late-onset colorectal cancer.
Authors: Myra E. Green, Benjamin Adam Weinberg
Journal: Journal of Clinical Oncology (2023)

208 Background: Early-onset colorectal cancer (CRC) is a growing public health problem with an incidence rate increase of 7.9% in individuals aged 20-29, 4.9% in those aged 30-39, and 1.6% in those aged 40-49 during 2004-2016. The etiology of this rise is not well established, but there is emerging evidence that the intra-tumoral microbiome may be implicated. We sought to categorize the interaction between diet and intra-tumoral microbiome in early- vs. late-onset CRC. Methods: Intra-tumoral microbiome data were collected from patients enrolled in a retrospective/prospective study of early ( &lt; 45 years) vs. late-onset (≥ 65 years) CRC. Formalin-fixed paraffin-embedded tumor samples were microdissected for tumor vs. non-tumor, then DNA was extracted and analyzed using 16S ribosomal gene sequencing. The DHQ3 diet questionnaire was used to ascertain diet history for a period of 12 months prior to diagnosis. Twelve bacteria of interest were selected for analysis based on increased prevalence and known potential association with CRC. Diet groups of interest for analysis included high-risk groups: fried foods, red meat, and alcohol. Results: A subset of 3 bacteria were further analyzed, Bacillus sp., Fusobacterium nucleatum, and Moraxella osloensis, based on relation to the group of patients diagnosed with CRC before the age of 45 (N = 8) and after age 65 (N = 12). Bacteria of interest had a similar prevalence in early- (38%, 3/8) and late-onset patients (33%, 4/12). Fifteen of the 20 patients had one or more of the bacteria of interest present. 71% (5/7) of both early- and late-onset patients who had Bacillus present had no alcohol in their diets. 100% (4/4) of the late onset patients with Bacillus present all had the same diet pattern: no tree nuts, high amounts of potato chips, no alcohol, and no red meat. 83% (5/6) of the early onset patients with 1 or more bacteria present had a high amount of potato chips in their diets. 80% (4/5) patients who had none of the bacteria of interest present also had no red meat in their diet. All early- and late-onset patients with Moraxella had a diet that consisted of more high-risk food groups, in particular potato chips. Conclusions: There were no significant differences in intra-tumoral microbiome in patients with early- vs. late-onset CRC. However, there may be an association between certain bacteria and high-risk diets. Results were limited by a small sample size, and further research should be done to better understand the relationship between intra-tumoral microbiome and diet.
Immunohistochemical assessment of COX2, P53, and beta-catenin expression to predict metachronous lesion development following polypectomy.
Authors: Mark Scott Johnstone, Sara SF Al-Badran, Reiss Stoops, Jennifer Hay, Jakub Jawny, Gerard Lynch, Stephen T McSorley, Joanne Edwards
Journal: Journal of Clinical Oncology (2023)

234 Background: Following colorectal polypectomy, 20-50% develop metachronous polyps, and some have increased colorectal cancer (CRC) risk. Surveillance colonoscopy is recommended to high-risk patients, based on index polyp number, histology and size. We aimed to assess if COX2, p53 and beta-catenin expression could predict metachronous polyp/ CRC risk. Methods: Tissue microarrays (TMA’s) were constructed for 339 patients from the INCISE study, a retrospective analysis of all patients undergoing screening polypectomy (Apr’09-Dec’16) followed by surveillance (6months-6years) in Glasgow, UK. Epithelial COX2, p53 and beta-catenin expression were assessed for each patient’s most advanced index polyp using immunohistochemistry, quantified by QuPath software. Kaplan-Meier analysis, log-rank tests and univariate/ multivariate cox regression assessed the association between marker expression and time to metachronous polyp/ CRC detection. Results: Low nuclear p53 expression was associated with shorter time to metachronous polyp/ CRC detection (p=0.024). Low nuclear (p=0.012) and membranous (p=0.046) beta-catenin expression was associated with shorter time to metachronous polyp/ CRC detection. There was no association between cytoplasmic COX2 expression and time to metachronous polyp/ CRC detection overall (p=0.309), but high cytoplasmic COX2 expression was associated with shorter time to detection of advanced metachronous lesions (advanced colorectal polyps/ CRC) (p=0.011). A combined score using the two most powerful biomarkers (nuclear p53 and nuclear beta-catenin – both high/ one low/ both low) was also associated with shorter time to metachronous polyp/ CRC detection (p=0.011). Univariate and multivariate cox regression are shown. Conclusions: Index polyp number and combined nuclear p53/beta-catenin expression independently predicted time to metachronous polyp/ CRC detection. [Table: see text]